OA12731A - Controlled release polymeric compositions of bone growth promoting compounds. - Google Patents
Controlled release polymeric compositions of bone growth promoting compounds. Download PDFInfo
- Publication number
- OA12731A OA12731A OA1200400150A OA1200400150A OA12731A OA 12731 A OA12731 A OA 12731A OA 1200400150 A OA1200400150 A OA 1200400150A OA 1200400150 A OA1200400150 A OA 1200400150A OA 12731 A OA12731 A OA 12731A
- Authority
- OA
- OAPI
- Prior art keywords
- composition
- compound
- polymer
- amino
- phenoxy
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Materials For Medical Uses (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Compositions Of Macromolecular Compounds (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention is directed to an improved system for controlled release of a bone growth promoting compound and to a flowable composition for its formation. The flowable composition is composed of a bone growth promoting compound, a thermoplastic polymer and an organic solvent. The flowable composition is capable of forming a biodegradable and/or bioerodible microporous, solid polymer matrix. The matrix is useful as an implant in patients (humans and animals) for delivery of a bone growth promoting compound to certain tissues.
Description
012731 -1-
CONTROLLED RELEASE POLYMERIC COMPOSITIONS OF BONEGROWTH PROMOTING COMPOUNDS
FIELD OF THE INVENTION
The invention is directed to an improved System for the controlled release of a5 bone growth promoting compound and to a flowable composition for its formation.The flowable composition is composed of a thermoplastic polymer, a bone growthpromoting compound and an organic solvent. The flowable composition is capable of forming a biodégradable and/or bioerodible microporous, solid polymer matrix.The matrix is useful as an implant in patients (humans and animais) for delivery of a 10 bone growth promoting compound to bone tissues.
BACKGROUND OF THE INVENTION
Biodégradable polymers are useful in many medical applications, especlallydrug delivery devices. Many of the biodégradable polymers used are of thethermoplastic type. Polymers made of thermoplastic resins typically liquify or soften 15 at elevated températures and resolidify upon cooling. This type of polymer isgenerally formed into the desired structure for use as sutures, surgical clips,
Staples, implants and the like, prior to insertion into the body. Once inserted into thebody, these polymers retain theïr shape.
For drug delivery devices, the drug is generally incorporated into the polymeric 20 composition and formed into the desired shape outside the body. This solid implantis then typically inserted into the body of a human, animal, bird or the like throughan incision. Alternatively, small discrète particles composed of these polymers canbelnjected into the body by a syringe. Preferably, however, certain of these _polymers can be injected via syringe as a flowable polymeric composition. 25 Flowable polymeric compositions for use as biodégradable controlled releasedrug delivery Systems are described in the patent literature, e.g., U.S. Pat. Nos.4,938,763; 5,077,049; 5,324,519; 5,632,727; 5,599,552; 5,702,716; 5,487,897;5,660,849; 5,278,201; 5,198,220; 5,447,725; 5,242,910; 5,733,950; 5,739,176;5,945,115; 5,744,153; 5,759,563; 5,660,849; and 6,143,314. 30 These compositions are administered to the body in a flowable physical state,typically via syringe. Once in the body the composition transforms into a solid. Onetype of polymeric composition consists of a nonreactive thermoplastic polymer orcopolymer dissolved or dispersed in an organic solvent. This polymeric solution isplaced into the body where the polymer gels or precipitatively solidifies upon the 012731 -2- dissipation or diffusion of the solvent into the surrounding body tissues. Also,improved polymeric compositions that form a solid matrix in situ thereby forming animplant for sustained reiease of a médicament over a desired period of time aredescribed in the patent literature. 5 An example of a commercially available product that utilizes this technology isthe ATRIDOX™ product which is a subgingival controlled-release productcomposed of a two syringe mixing System. Syringe A contains 450 mg of theATRIGEL® Delivery System, which is a bioabsorbable, flowable polymericformulation composed of 36.7% poly(DL-lactide)(PLA) dissolved in 63.3% N- 10 methyl-2-pyrrotidone (NMP). Syringe B contains the antibiotic doxycycline hyclatewhich is équivalent to 42.5 mg doxycycline. K.P. Andriano et al., J. Biomed. Mater. Res. (Appl. Biomater.), 53: 36-43 (2000),disclose preliminary in vivo studies on the ostéogénie potential of bonemorphogenetic proteins delivered from an absorbable puttylike polymer matrix. R.L. 15 Dunn et al., Portland Bone Symposium 1999, Oregon Health Sciences University,pages 522 to 528, studied the osteoinductivity of bone morphogenetic proteinsdelivered from an absorbable putty-like matrix.
The optimal contrai of reiease rate of certain bone growth promotingcompounds, especially certain small molécule, is a never-ending quest for 20 sustained reiease implants including but not limited to the flowable compositions.Consequently, there is the need for a flowable composition in which the rate ofdelivery of certain bone growth promoting compounds can be more readilycontrolled, especially for a compound which requires sustained reiease over alonger time period.
25 SUMMARY OF THE INVENTION
It is an object of the présent invention to provide improved polymeric compositions in which the rate of reiease of a bone growth promoting compound isbalanced against the rate of dégradation of the polymer. It is a further object of theprésent invention to provide improved polymeric compositions which form an 30 implant in situ that dégradés quickly enough so as to not impede bone growth at thedesired site.
The présent invention provides the following: A pharmaceutical composition suitable for in situ formation of an implant in apatient comprising: 012731 -3- (a) a pharmaceutically acceptable, biodégradable thermoplastic polymer orcopolymer that is insoluble in aqueous or body fluid; (b) a biocompatible organic solvent which solubilizes the thermoplastic polymer,is dispersible in situ in body fluid, is highly soluble in water and is capable of 5 dissipating from the polymer System into surrounding tissue fluid whereupon thethermoplastic polymer forms the implant; and (c) a therapeutically effective amount of a compound or a pharmaceuticallyacceptable sait thereof selected from the group consisting of: (3-(((4-ie/ï-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetÎc 10 acid; 7-[(4-butyl-benzyl)-'methanesulfonyl-amino]-heptanoic acid; and7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoicacid.
More particularly, the présent invention provides the above composition wherein the composition forms a controlled release implant at or near the site of local 15 administration. Also, the présent invention provides the above composition whereinthe composition forms a controlled release implant at or near the site of the bonefracture, bone injury or bone defect.
More particularly, the présent invention provides the above composition whereinthe compound is the sodium sait of (3-(((4-fert-butyl-benzyl)-(pyridine-3-sulfonyl)- 20 amino)-methy!)-phenoxy)-acetic acid. Also, the présent invention provides theabove composition wherein the compound is the free acid of (3-(((4-ferf-biityl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-aœtic acid.
More particularly, the présent invention provides the above composition whereinthe-.amount of the compound is between about 5 to about 50 mgA/ml of the 25 composition. Even more particularly, the présent invention provides the abovecomposition wherein the amount of the compound is about 5, 10 or 50 mgA/ml ofthe composition.
More particularly, the présent invention provides the above composition whereinthé polymer is selected from the group consisting of polylactides, polyglycolides and 30 copolymers thereof. More particularly, the présent invention provides the abovecomposition wherein the copolymer has an inhérent viscosity of about 0.20 dl/g toabout 0.40 dl/g. Even more particularly, the présent invention provides the abovecomposition wherein the copolymer has an inhérent viscosity of about 0.20 dl/g. 012731 -4-
More particularly, the présent invention provides the above composition whereinthe copolymer is poly-iactic-co-glycolic acid (PLGH). Even more particularly, theprésent invention provides the above composition wherein the ratio of lactic acid toglycolic acid is about 1 to about 1.
More particularly, the présent invention provides the above composition whereinthe copolymer is polyethylene glycol (PEG) end-capped poly-lactic-co-glycolic acid(PLGH). Even more particularly, the présent invention provides the abovecomposition wherein the weight % of PEG to PLGH is between about 3 to about5%.
More particularly, the présent invention provides the above composition whereinthe solvent is N-methyl-2-pyrrolidone (NMP). Even more particularly, the présentinvention provides the above composition wherein the copolymer is poly-lactic-co-glycolic acid (PLGH) and wherein the solvent is N-methyl-2-pyrroIidone (NMP). Theprésent invention provides such composition wherein the weight percentage ofPLGH to NMP in solution is between about 30% and about 60% of PLGH tobetween about 70% and about 40% of NMP. Even more particularly, the présentinvention provides the above composition wherein the weight percentage of PLGHto NMP in solution is selected from the following: about 37% PLGH to about 63%NMP; about 45% PLGH to about 55% NMP; about 50% PLGH to about 50% NMP;and about 55% PLGH to about 45% NMP. Most particularly, the présent inventionprovides the above composition wherein the weight percentage of PLGH to NMP insolution is about 50% PLGH to about 50% NMP.
In addition, the présent invention provides a pharmaceutical kit suitable for insituiormation of a biodégradable implant in the body of a patient, which comprises: A) a device containing a compound or a pharmaceutically acceptable saitthereof selected from the group consisting of: (3-(((4-terf-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid; 7-[(4-butyl-benzyI)-methanesulfonyl-amino]-heptanoic acid; and 7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid; and B) a device containing a flowable composition of a biodégradable,biocompatible, pharmaceutically acceptable thermoplastic polymer that is insolublein aqueous or body fluid and a pharmaceutically acceptable solvent that isdispersible in situ in body fluid and is highly water soluble, wherein the 012731 -b- concentrations and formulas of the polymer and the solvent in the flowablecomposition are effective to form an implant in situ when the flowable compositioncontacts body fluid; C) wherein the devices hâve an outlet for the compound or the flowable5 composition, an ejector for expelling the compound or the flowable composition through the outlet and a hollow tube fitted to the outlet; and wherein the contents ofthe two devices are mixed together immediately prior to delivering the contents ofthe device containing the mixture into the body of the patient.
More particularly, the présent invention provides the above pharmaceutical kit 10 wherein the concentrations and formulas of the polymer and the solvent areeffective to form a space filling implant in the body of the patient.
More particularly, the présent invention provides the above pharmaceutical kitwherein the polymer is selected from the group consisting of polylactides andcopolymers thereof with glycolide. Even more particularly, the présent invention 15 provides the above pharmaceutical kit wherein the copolymer is poly-lactic-co-glycolic acid (PLGH). Even more particularly, the présent invention provides theabove pharmaceutical kit wherein the ratio of lactic acid to glycolic acid is about 1 toabout 1.
More particularly, the présent invention provides the above pharmaceutical kit 20 wherein the solvent is N-methyl-2-pyrrolidone (NMP). More particularly, the présentinvention provides the above pharmaceutical kit wherein the compound is in thelyophilized form.
Also, the présent invention provides a method of forming an implant in-situ, in aliving body, comprising the steps of: . 25 (a) dissolving a non-reactive, water-insoluble biodégradable polymer in a biocompatible, highly water soluble organic solvent that is dispersible in body fluidin situ to form a flowable composition; (b) adding an effective amount of a compound to the flowable composition toprovide a pharmaceutical composition; 30 (c) placing the pharmaceutical composition within the body; and (d) allowing the solvent to dissipate to produce a solid or gel implant which releases the compound by diffusion, érosion or a combination of diffusion andérosion as the implant biodegrades; 012731 -6- wherein the compound or a pharmaceutically acceptable sait thereof is selectedfrom the group consisting of: (3-(((4~teff-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid; 7-[(4-butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid; and7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid;wherein the polymer is selected from the group consisting of polylactides and copolymers thereof with glycolide; and wherein the solvent is N-methyl-2-pyrrolidone (NMP).
More particulariy, the présent invention provides the above method wherein thecopolymer is poly-lactic-co-gfycolic acid (PLGH). More particulariy, the présentinvention provides the above method which further comprises delivering said liquidin-situ through a syringe. More particulariy, the présent invention provides theabove method wherein the implant is formed at or near a bone fracture, bone defector bone injury in the body. Also, the présent invention provides a biodégradabledrug delivery implant for a body produced according to the above method.
In addition, the présent invention provides a kit for achieving a therapeutic effectin a mammal which has been prescribed the joint administration of the ingrédientsdesignated as (1) and (2) below, each ingrédient forming a portion of said kit,comprising in association: (1) a therapeutically effective amount of an active ingrédient, said activeingrédient being (3-(((4-ferf-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid; 7-[(4-butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid;or 7-{[2-(3,5-dichloro-phenoxy)-ethylj-methanesulfonyl-amino}-heptanoic acid_; or apharmaceutically acceptable sait thereof and a pharmaceutically acceptable carrieror diluent in a first unit dosage form; (2) a flowable composition of a biodégradable, biocompatible, pharmaceuticallyacceptable thermoplastic polymer that is insoluble in aqueous or body fluid and apharmaceutically acceptable, highly water soluble solvent that is dispersible in situin body fluid, wherein the concentrations and formulas of the polymer and thesolvent in the composition are effective to form an implant in situ when saidcomposition contacts body fluid; in a second unit dosage form; and (3) directions for the administration of the ingrédients (1) and (2) in a manner toachieve the desired therapeutic effect. -7-
More particularly, the présent invention provides the above kit wherein theactive ingrédient is the sodium sait of (3-(((4-fe/ï-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid. More particularly, the présent inventionprovides the above kit wherein the active ingrédient is the free acid of (3-(((4-terf- 5 butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid.
More particularly, the présent invention provides the above kit wherein thepolymer is selected from the group consisting of polylactides, polyglycolides andcopolymers thereof. Even more particularly, the présent invention provides theabove kit wherein the polymer is selected from the group consisting of polylactides 10 and copolymers thereof with glycolide. Even more particularly, the présent inventionprovides the above kit wherein the copolymer is poly-lactic-co-glycolic acid (PLGH).Even more particularly, the présent invention provides the above kit wherein theratio of lactic acid to glycolic acid is about 1 to about 1.
More particularly, the présent invention provides the above kit wherein the 15 solvent is N-methyI-2-pyrrolidone (NMP). Also, the présent invention provides theabove kit wherein the compound is in the lyophilized form.
The présent invention is directed to a polymer System for spécifie bone growthpromoting compounds, a method for therapeutic treatment using such polymerSystem and a precursor of such polymer System, a flowable composition. 20 The présent invention provides a flowable composition that provides sustainedrelease at the local site of injection (e.g., bone fracture site, bone defect site, boneinjury site) by forming a biodégradable solid or gel implant. More particularly, theprésent invention provides a composition and method for delîvering a bone growthpromoting compound in a slow-release biodégradable polymer based delivery 25 System, which is preferably injectable.
The polymer System is a microporous, solid or gel matrix of a biocompatible, biodégradable thermoplastic polymer and a bone growth promoting compound.
The system of the présent invention provides for optimal control of the rate andextent of release of the bone growth promoting compound from the matrix. The 30 flowable composition contains an organic solvent, â biocompatible, biodégradablethermoplastic polymer and a bone growth promoting compound.
The polymer system is formed by applying the flowable composition to either oftwo gélation media: a) body fluid that is internai to the body, and b) a water mediumthat is external to the body. After application, the flowable composition gels or 012731 -8- coagulates to form the polymer System. Administration of the flowable compositiondirectly into the body forms in situ the polymer System. External addition of theflowable composition to a water medium forms the polymer System outside thebody. The solid implantable polymer System formed outside the body can then besurgically placed into the body. In ail embodiments and applications, the polymerSystem is substantially insoluble in water, water solutions and body fluid.
The process by which the polymer System is formed in part is reSponsible fordevelopment of the rate and release control. Interaction of the flowablecomposition with body fluid in situ in the body to coagulate or gel the compositioninto the polymer System at least in part causes the desired controlled release profileas a function of the variation of the below-mentioned parameters and components.Simple combination of these components without passage through the flowablecomposition wili not develop the controlled release profile of the présent invention.When the flowable composition is contacted by body fluid in situ, the organicsolvent diffuses into the surrounding medium (body fluids) and the polymercoagulâtes or gels to form the solid or gel matrix (polymer System). Because thebody fluid contains lipophilie components and dynamically flows around theflowable composition, the coagulation or gelling occurs when the organic solventhas a water solubility ranging from highly soluble to insoluble.
When the composition of the présent invention is placed in the body, it isretained localiy at the site of the fracture, defect or injury. The resulting polymerSystem may adopt the shape of the bone fracture, defect of injury into which thecomposition is placed.
Pursuant to the parameters and conditions of the présent invention, the polymerSystem can control the sustained release of a bone growth promoting compound invivo. In particular, the rate and extent of release of the bone growth promotingcompound from the polymer System of the présent invention are controlled over anarrow range of speeds and amounts. This control is accompiished by variation of:(a) the polymer type and molecular weight, (b) the concentration of the polymer, (c)the concentration of the bone growth promoting compound, and (d) the form of thebone growth promoting compound. Preferably, the rate and extent of release of thebone growth promoting compound from the polymer System according to theprésent invention can be controlled by varying: (1) the type and molecular weight ofthe polymer or polymers, and/or (2) the concentration of the polymer. 012731 -9- -, s ο ·
More preferably, the contrai is accomplished by varying the molecular weight ofthe polymer. In preferred embodiments, the rate of release increases as polymermolecular weight decreases.
The method of the présent invention is based upon the therapeutic effect of thein situ controlled release of the bone growth promoting compound from the polymerSystem. The implantation of the flowable composition occurs at or near the site ofthe bone fracture, bone defect or bone injury in the body of a patient in need oftherapeutic treatment. For example, it may be implanted in the bone fracture sothat it adapts and conforms to the shape of the fracture. Preferably, it is implantedin the soft tissue, such as muscle or fat, at or near the site of the bone fracture,defect or injury. The composition can be administered to the implant site by anysuitable method for applying a flowable composition, as for example, by means of asyringe, needle, cannula or cathéter. The polymer System preformed as an implantcan be inserted by known surgical techniques.
DETAILED DESCRIPTION OF THE INVENTION
The présent invention relates to a polymer System for the controlled delivery ofa bone growth promoting compound, a flowable composition for producing suchSystem, and a method for use of such a System in therapeutic treatment. Thepolymer System of the présent invention is advantageous in that it can bemanipulated to control the amount of bone growth promoting compound releasedand the rate at which it is released in vivo.
The présent invention provides an injectable, flowable composition that providessustained release at the local site of the injection (e.g., bone fracture site, bonedefect site, bone injury site) by forming a biodégradable solid or gel depot, matrix orimplant.
More particuiarly.’the présent invention provides a composition and method fordelivering a bone growth promoting compound in a slow-release biodégradablepolymer based delivery System.
The polymer based delivery System contains a bone growth promotingcompound dissolved or dispersed in biodégradable, thermoplastic polymer solutionor dispersion in an organic solvent. Upon injection of the flowable composition, theorganic solvent diffuses away from the injection site, causing the polymer toprecipitate or gel; thereby entrapping the compound in a sustained-release depot.The compound is subsequently released by diffusion from, and érosion of, the 012731 -10- polymeric matrix. The polymeric matrix slowly erodes by hydrolysis and eventuallydisappears from the site of administration. The molecular weight and concentrationof the polymer can control the in vivo release of the compound as well as thedégradation rate of the matrix.
The polymer based delivery System of the présent invention provides sustainedrelease of a bone growth promoting compound in vivo for a sustained period of timewith minimum or reduced burst that is efficacious in promoting bone growth in apatient in need thereof. A large burst of compound would resuit in poor localtoleration due to local effects of the compound (e.g., irritation) and would minimizethe amount of compound availabie for efficacy. The advantages of thecompositions of the présent invention are that they minimize or reduce the initiaiburst but still deliver compound at efficacious levels for a sustained period of timeupon a single local injection.
The polymer system is prepared by contacting the flowable composition with agélation medium to coagulate or gel the composition into a solid, microporouspolymeric matrix or a gel polymeric matrix. The flowable composition contains athermoplastic polymer or copolymer in combination with a suitable solvent. Thepolymers or copoiymers, which form the body of the matrix, are substantialiyinsoluble, preferably essentially completely insoluble, in water and body fluids. Theinsolubility of the matrix body enables it to function as a single site for the controlledrelease of the bone growth promoting compound. The polymers or copoiymers alsoare biocompatible and biodégradable and/or bioerodible within the body of ananimal, e.g., mammal. The biodégradation enables the patient to metabolize thepolymer matrix so that it can be excreted by the patient without the need for fürthersurgery to remove it. Because the flowable composition and polymer system arebiocompatible, the insertion process and the presence of the polymer system withinthe body do not cause substantial tissue irritation or necrosis at the implant site.
The composition of the présent invention is administered as a flowable compositiondirectly into body tissues, e.g., soft tissue at or near the bone defect or bonefracture site, wherein an implant of the polymer system is formed in situ.
The term "patient” means an animal, such as a human, a companion animal, such as a dog, cat and horse, and livestock, such as cattle, swine and sheep.
Particularly preferred patients are mammals, inciuding both males and females, with humans being even more preferred. 0127 31 -11-
The bone growth promoting compounds of the présent invention are thefollowing: (3-(((4-ferf-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-aceticacid, including its free acid and its pharmaceutically acceptable salts, such as thesodium sait. This compound and pharmaceutically acceptable salts thereof may beprepared according to the synthetic méthodologies described in publishedInternational patent application WO 99/19300, which are incorporated by référencéherein. 7-î(4-butyl-benzyl)-methanesulfonyl-amino]-heptanoic acid and its *pharmaceutically acceptable salts. This compound and pharmaceuticallyacceptable salts thereof may be prepared according to the synthetic méthodologiesdescribed in published International patent application WO 98/28264, which areincorporated by référencé herein. 7-{[2-(3,5-dichIoro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid andits pharmaceutically acceptable salts. Thiscompound and pharmaceuticallyacceptable salts thereof may be prepared according to the synthetic méthodologiesdescribed in published International patent application WO 98/28264, which areincorporated by référencé herein.
The above three compounds are capable of promoting growth and survival ofbone cells and tissues, or augmenting the activity of functioning bone cells andtissues and bone marrow and the like.
Suitable thermoplastic polymers for incorporation into the solid matrix of thecontrolled release polymer System are solids, pharmaceutically compatible andbiodégradable by cellular action and/or by the action of body fluids. Examples ofappropriate thermoplastic polymers include polyesters of diol§ and dicarboxylicacids or of hydroxycarboxylic acids, such as polylactides, polyglycoiides andcopolymers thereof. More preferably the polymer is the copolymer, poly-lactic-co-glycolic acid (abbreviated PLGH), which upon hydrolysis, produces lactic andglycolic acid. The burst of release of this copolymer can be minimized further bythe addition of polyethylene glycol (PEG) to form the PEG end-capped PLGH.
Preferred materials for use in the présent invention are the polylactides, polyglycoiides and copolymers thereof. These polymers can be used to advantage in the polymer System in part because they show excellent biocompatibility. They produce little, if any, tissue irritation, inflammation, necrosis or toxicity. In the 012731 -12- presence of water, these polymère produce lactic and glycolic acid, respectively,which are readily metabolized by the body. The polylactides can also incorporateglycolide monomer to enhance the resulting polymer's dégradation. Thesepolymère can aiso be used to advantage in the polymer System of the présent 5 invention because they effectively control the rate of release of the bone growthpromoting compound from the polymer System and because they resuit in the localrétention of the bone growth promoting compound at the site of the bone fracture,defect or injury. These polymère are also preferred because they dégradé quicklyenough from the site of the bone fracture, defect or injury so as to not impede bone 10 growth at the site of the bone fracture, defect or injury.
The solubility or miscibility of a thermoplastic polymer in the organic solvent of the composition will vary according to factors such as crystallinity, hydrophifïcity,capacity for hydrogen bonding and molecular weight of the polymer. Consequently,the molecular weight and the concentration of the polymer in the solvent are 15 adjusted to achieve desired miscibility, as well as a desired release rate for theincorporated bone growth promoting compound.
According to the practice of the présent invention, the flowable composition ofthermoplastic polymer, solvent and the bone growth promoting compound is astable flowable substance, in the présent invention, a homogenous solution of the 20 bone growth promoting compound in an organic solvent preferably results. Thethermoplastic polymer is substantially soluble in the organic solvent. Uponplacement of the flowable composition into the body, the solvent will dissipate andthe polymer will solidify or gel to form the polymer System having the bone growthpromoting compound within a solid or gel polymeric matrix. 25 While not intending to limit the présent invention to a spécifie mechanism of ·action, it has been discovered that the molecular weight of the polymer used in theprésent invention distinctly affects the rate of release of the bone growth promotingcompound and the rate of dégradation of the polymer from the site of the bonefracture, defect or injury as long as the flowable composition has been used as an 30 intermediate.
For certain preferred polymère for use in the présent invention, the molecularweight of the polymer or copolymer is adjusted to be within a range of about 0.2 toabout 0.4 inhérent viscosity (I.V, in deciliters/g) for effective sustained release of thebone growth promoting compound. The typical rate of release of the incorporated 012731 -13- bone growth promoting compound occurs at an I.V. of about 0.2 (about 8,000 toabout 16,000 molecular weight) or about 0.3 (about 23,000 to about 45,000molecular weight) but can vary depending on the particular components of thecomposition. For most Systems, it is preferred to adjust the molecular weight of thepoiymer to about 0.2 I.V. for an effective sustained release of the bone growthpromoting compound. The unit of measure for the molecular weight is daltons.
For a poly(DL-lactide) or a lactide-co-giycolide poiymer System, the desiredmolecular weight range is about 0.2 to about 0.4 I.V., with an I.V. of about 0.2 beingmost preferred. The molecular weight of a poiymer can be varied by any of a varietyof methods. The choice of method is typically determined by the type of poiymercomposition. The preferred polymers for use in the présent invention arecommercially available.
Highly preferred thermoplastic polymère for use in the présent invention are thefollowing: PLGH copolymer with 1:1 ratio of lactic and glycolic acid with an inhérentviscosity of about 0.2 dl/g (commercially available from Boehringer Ingelheim asCopolymer RESOMER® RG 502 H) (about 12,000 molecular weight); PLGHcopolymer with 1:1 ratio of lactic and glycolic acid with an inhérent viscosity ofabout 0.3 di/g (commercially available from Boehringer Ingelheim as CopolymerRESOMER® RG 503 H)(about 37,000 molecular weight); PLGH copolymer with 1:1ratio of lactic and glycolic acid with an inhérent viscosity of about 0.4 dl/g(commercially available from Boehringer Ingelheim as Copolymer RESOMER® RG504 H) (about 47,000 molecular weight); and polyethylene glycol (PEG) end-capped PLGH copolymer with 1:1 ratio of lactic and glycolic acid with an inhérentviscosity of about 0.79 dl/g (commercially available from Boehringer Ingelheim asPLG-PEG) (about 52,000 molecular weight).
By appropriate choice of the poiymer molecular weight and viscosity, the rateand extent of release of the bone growth promoting compound of the présentinvention from the poiymer System can be varied from very fast to very slow. Forexample, according to the présent invention, the release rate of the bone growthpromoting compound, (3-(((4-fe/f-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid, sodium sait, can be slowed to produce substantially complétérelease of the compound within about seven days. With the use of a greaterviscosity of poiymer according to the présent invention, the period of time can beincreased to about fourteen days. The desired release rate of the bone growth 012731 -14- promoting compound will dépend on several factors, such as fhe species of animalbeing treated as well as the spécifie condition being treated.
The concentration of the polymer in the System can also be varied to adjust therelease rate of the incorporated bone growth promoting compound. lt has been 5 discovered that the more dilute the polymer concentration, the more readily thebone growth promoting compound will be released. This effect can be used incombination with other methods to more effectively control the release of theincorporated bone growth promoting compound as desired. For exampie, byadjusting the concentration of the polymer and the bone growth promoting 10 compound, if desired, a wide range of release rates can be obtained
The solvents used in the thermoplastic compositions of the présent invention are preferabiy pharmaceutically acceptable, biocompatible and will dissîpate intobody fluid in situ such that they may be classed as having a solubiiity in waterranging from highly soluble to insoluble. Preferabiy, they cause relatively little, if 15 any, tissue irritation or necrosis at the site of the injection and implantation.Preferabiy, the solvent may hâve at least a minimal degree of water solubiiity.
When the organic solvent is water insoluble or is minimally soluble in water, thesolvent will slowly disperse from the flowable polymeric composition. The resuit willbe an implant that during the course of its life may contain a varying amount of 20 residual solvent. Especially preferabiy, the organic solvent has a moderate to highdegree of water solubiiity so that it will facilely disperse from the polymericcomposition into the body fluids. Most preferabiy, the solvent disperses rapidly fromthe polymeric composition so as to quickly form a solid implant. Concomitant withtheTlispersion of solvent, the thermoplastic polymer coagulâtes or gels into the solid 25 polymer System. Preferabiy, as the thermoplastic polymer coagulâtes, the solventdispersion causes pore formation within the polymer System. As a resuit, theflowable composition containing thermoplastic polymer, solvent and bone growthpromoting compound will form a porous solid polymer System. Also, when thesolvent is slightly water soluble or is water insoluble, the solvent dispersion may 30 resuit in the formation of a solid porous implant, or if some solvent remains with theimplant, the resuit may be formation of a gel implant having few or no pores.
Suitable solvents include those liquid organic compounds meeting the foregoingcriteria. The preferred solvent for use in the présent invention is N-methyl-2- 012731 -15- ι pyrrolidone (NMP) due, at least in part, to its solvating ability and itsbiocompatibility.
The solvents for the thermoplastic polymer flowable compositions of the présentinvention are chosen for compatibility and appropriate solubility of the polymer andsolvent. Lower molecular weight thermoplastic polymers will normaliy dissolve morereadily in the solvents than high molecular weight polymers. As a resuit, theconcentration of a thermoplastic polymer dissolved in the various solvents differsdepending upon type of polymer and its molecular weight Conversely, the highermolecular weight thermoplastic polymers will tend to coagulate, gel or solidify fasterthan the very low molecular weight thermoplastic polymers. Moreover, the highermolecular weight polymers tend to give higher solution viscosities than the lowmolecular weight materials. Thus, for advantageous injection effieîency, in additionto advantageous release rate, the molecular weight and the concentration of thepolymer in the solvent are controlled.
Upon formation of the polymer System from the flowable composition, the bonegrowth promoting compound becomes incorporated into the polymer matrix. Afterinsertion of the flowable composition to form in situ the polymer System, the bonegrowth promoting compound will be released from the matrix into the adjacenttissues or fluids by diffusion and polymer dégradation mechanisms. Manipulation ofthese mechanisms also can influence the release of the bone growth promotingcompound into the surroundings at a controlled rate. For example, the polymermatrix can be formulated to dégradé after an effective and/or substantial amount ofthe bone growth promoting compound is released from the matrix. Thus, therelease of the bone growth promoting compound from the matrix can be varied by,for example, the solubility of the bone growth promoting compound in water, thedistribution of the bone growth promoting compound within the matrix, or the size,shape, porosity, solubility and biodegradability of the polymer matrix, among otherfactors. The release of the bone growth promoting compound from the matrix iscontrolled relative to its inhérent rate by varyihg the polymer molecular weight toprovide a desired duration and rate of release.
The polymer System is formulated to contain a bone growth promoting compound in an amount effective to provide a desired biological, physiological and/or therapeutic effect. More particularly, the polymer System of the présent invention is formulated to contain a bone growth promoting compound in an amount 012731 -16- effective to promote the growth and survival of bone cells and tissues, and/oraugment the activity of functioning bone cells and tissues and bone marrow and thelike.
The "therapeutically effective amount" of a bone growth promoting compoundincorporated into the polymeric composition of the présent invention dépends on avariety of factors, such as the desired release profile, the concentration of bonegrowth promoting compound required for a desired biological effect, and the periodof time over which the bone growth promoting compound needs to be released fordesired treatment. Ultimately, this amount is determined by the human or animalpatient's physician or veterinarian, respectively, who will apply his expérience andwisdom in prescribing the appropriate kind.and amount of bone growth promotingcompound to provide therapy for the patient. There is generally no critical upperlimit on the amount of bone growth promoting compound incorporated into thepolymer solution. The only limitation is a physical limitation for advantageousapplication, i.e., the bone growth promoting compound should not be présent insucha high concentration that the solution or dispersion viscosity is too high forinjection. The lower limit of the bone growth promoting compound incorporated intothe polymer System typically dépends only on the activity of the bone growthpromoting compound and the period of time desired for treatment.
Preferably, a therapeutically effective amount for the bone growth treatment forthe bone growth promoting compounds of the présent invention range betweenabout 0.001 to about 100 mg/kg/day, with an especially preferred amount beingabout 0.01 to about 10 mg/kg/day.
Administration of the flowable composition of the présent invention ultimatelywill be accomplished according to the wisdom and protocol of the patient’sattending health care professional such as a physician, or if appropriate, a DVM.Choice of the particular composition will dépend upon the condition to be treated,which choice will be made by the attending health care professional. For example,with hard tissue such as bone, the biodégradable polymer containing a bone growthpromoting compound supports the growth of new bone cells. These new bone cellseventually replace the degrading polymer.
For example, a preferred dosage form of the bone growth promoting compound, (3-(((4-fe/ï-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid,
is a lyophiie of the sodium sait to be reconstituted with a solution of PLGH in NMP 012731 before administration. The dosage form, consisting of the lyophilized compound inone syringe (syringe A) and a solution of PLGH in NMP in a second syrînge(syringe B), is known as the A/B reconstitution System. The contents of bothsyringes are mixed together immediately prior to dose delivery at or near thefracture site. After reconstitution, the contents are transferred into a graduateddosing syringe for delivery. The administered dosage forms will be a solution andwill resuit in the dispersion of the compound with PLGH in NMP at desired strengthsof, for example, 5 and 50 mgA/ml (mgA/ml refers to the free acid équivalent of thesodium sait form of the compound). The dosage form is a parentéral (e.g.,subcutaneous, intramuscular or intrameduliary) sustained release injection for localadministration. This compound in a slow-release polymer matrix (depot injection) isdesigned for administration at or near a fracture site or bone defect or injury, and isnot intended for intravenous administration. To provide adéquate shelf-life stabilityfor the dosage form, a two-syringe System (A/B), as described above, may be used,preferably with the sodium sait form of the compound. A uniphase formulation,preferably with the free acid form of the compound, is a preferred alternativeformulation. Based on the compound and polymer stability, stérile filtration of thecompound and irradiation of the polymer solution may be preferred formanufacturing a stable stérile product. In one embodiment, the dosage form can bemanufactured and shipped as separate aluminum pouches containing syringes filled with the lyophile form of the compound in one pouch and the polymer solutionin the other pouch. Delivery containers, Systems and methods for the lyophilizationof the bone growth promoting compounds of the présent invention to préparepharmaceutical compositions and kits are described in published International 'patent application, WO 01/73363, published 4 October 2001, which is incorporatedby référencé herein.
EXAMPLES
The following examples are set forth as représentative of the présent invention.These examples are not to be construed as limiting the scope of the invention asthese and other équivalent embodiments will be apparent in view of the présentdisclosure and accompanying daims.
EXAMPLE A
To obtain dosage form at strengths of 5 and 50 mgA/ml, the following combinations A) and B) of lyophile and polymer syringe, respectively, were used: 012731 -18- A) 5 mgA/ml (upon reconstitution) of (3-(((4-fe/f-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid, sodium sait formulation:
Drug Syringe A contained 4 mgA of the sodium sait lyophile in 1.25 ml malesyringe without graduations; and 5 Vehide Syringe B contained 0.8 ml 50% RG502H/50%NMP solution in 1.25 mlfemale syringe without graduations. B) 50 mgA/ml (upon reconstitution) of (3-(((4-fe/f-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid, sodium sait formulation:
Drug Syringe A contained 40 mgA of the sodium sait lyophile in 1.25 ml male10 (fat) B-D syringe without graduations; and
Vehicle Syringe B contained 0.8 ml 50% RG502H/50% NMP solution in 1.25 mlfemale (thin) syringe without graduations.
MgA refers to free acid équivalent of the sodium sait form of the compound;
The percentages used in these exemples are based on the weight of the 15 indicated ingrédients; RG502H is a PLGH copolymer with 1:1 ratio of lactic and glycolic acid withinhérent viscosity of 0.2 dl/gm, which is commercially available such as fromBoehringer Ingelheim as Copolymer RESOMER® RG 502 H. EXAMPLE 1 20 50% RG502H/50% NMP with 5 mgA/ml of sodium sait of (3-(((4-ferf-butyl- benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid, mixed A/B(polymer solution autoclaved, compound lyophilized) EXAMPLE 2 -50% RG502H/50% NMP with 10 mgA/ml of sodium sait of (3-(((4-ferf-bütyl- 25 benzyI)-(pyridine-3-suIfonyl)-aminô)-methyl)-phenoxy)-acetic acid, mixed A/B(polymer solution irradiated, compound lyophilized) EXAMPLE 3
50% RG502H/50% NMP with 50 mgA/ml of sodium sait of (3-(((4-ferf-butyI-bènzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid, mixed A/B 30 (polymer solution irradiated, compound lyophilized) EXAMPLE 4 47% RG502H/3% PLG-PEG/50% NMP with 50 mgA/ml of sodium sait of (3-(((4-tezf-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid,uniphase 012731 -19- EXAMPLE 5 47% RG503H/3% PLG-PEG/50% NMP with 50 mgA/ml of sodium sait of (3-(((4-te/f-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid,uniphase EXAMPLE 6 45% RG504H/55% NMP with 50 mgA/ml of sodium sait of (3-(((4-ferf-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid, uniphase EXAMPLE 7 37% RG503H/63% NMP with 50 mgA/ml of sodium sait of(3-(((4-terf-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid, mixed A/B(polymer solution autoclaved, compound lyophilized) EXAMPLE 8 37% RG503H/63% NMP with 50 mgA/ml of sodium sait of (3-(((4-/ezï-butyi-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid, mixed A/B(polymer solution irradiated, compound lyophilized) EXAMPLE 9 50% RG502H/50% NMP with 5 mgA/ml of (3-(((4-ferf-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid, uniphase
Evaluation of Test Compounds in Controlled Release FormulationsI. Rat Fémoral Transverse Fracture Model
Male Sprague-Dawley rats at 3 to 4 months of âge were used. The animaiswere anesthetized with ketamine and xylazine at doses of 100 and 10 mg/kg,respectively. The right hindlimb of each rat was shaved and cleaned. A 1 cmincision was made just latéral to the patella and the fémoral condyle was exposèd. A Kirschner wire (0.045" in diameter) was introduced into the intramedullary canalthrough the intercondylar portion to serve as an internai stabilization. The muscleincision was closed with Vicryl® and the skin incision was closed with stainlesssteel wound clips. The mid-diaphysis of the pinned fémur was fractured by meansof a three-point bending device driven by a dropped weight. The rats werepermitted full weight-bearing and unrestricted activîty after awakening fromanesthésia. The test agents were administered on various days after surgery bypercutaneous injection onto the fracture site. The animais were sacrificed onvarious days after treatment and the fémurs were collected for analysis. Fracturehealing was evaluated by using radiography, histomorphometry and biomechanical 012731 -20- test. (See, e.g., F. Bonnarens and T.A. Einhorn, “Production of a standard closedfracture in laboratory animal bone," Journal of Orthopaedic Research 2:97-101(1984).) II. Study Protocol and Results in the Rat Fémoral Fracture Model
Male Sprague-Dawley rats at 3 to 4 months of âge were subjected to right fémoral fracture. The rats of control group were injected with respective vehicle.The rats in the treatment group received single dose of test compound in acontrolled release formulation of the présent invention by percutaneous injection tothe fracture site immediately after surgery. The drug concentration was 50 mg/ml,injection volume was 300 ul, and the total dose was 15 mg/rat. The animais weresacrificed on day 21 and the fémurs were collected for radiographie assessments.The fémurs treated with the test compound had larger and denser calluses thanthose treated with vehicle as assessed by radiography. The data indicated that thetest compound stimulated callus formation and may be effective in enhancingfracture healing.
The following are some examples of polymer formulations, which showedpositive results in the Rat Fémoral Fracture Model: 50% RG502H/50% NMP with 50 mgA/ml of sodium sait of (3-(((4-fezï-butyl-benyl)-(pyridine-3-sulfonyI)-amino)-methyI)-phenoxy)-acetic acid, mixed A/B(polymer solution irradiated, compound lyophilized); 47% RG502H/3% PLG-PEG/50% NMP with 50 mgA/ml of sodium sait of (3-(((4-ferf-butyl-benyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid,uniphase; -, 47% RG503H/3% PLG-PEG/50% NMP with 50 mgA/ml of sodium sait ôf (3- (((4-ie/ï-butyl-benyl)-(pyridine-3-suIfonyl)-amino)-methyl)-phenoxy)-acetic acid,uniphase.
MgA refers to free acid équivalent of the sodium sait form of the compound;RG502H is a PLGH copolymer with 1:1 ratio of lactic and glycolic acid with an inhérent viscosity of 0.2 dl/gm, which is commercially available such as fromBoehringer Ingelheim as Copolymer RESOMER® RG 502 H; RG503H is a PLGH copolymer with 1:1 ratio of lactic and glycolic acid with an inhérent viscosity of 0.3 dl/g, which is commercially available such as from
Boehringer Ingelheim as Copolymer RESOMER® RG 503 H. III. Rat Periosteal Injection Model 012731 -21-
Male Sprague-Dawley rats at 3 weeks of âge were used. The rats wereanesthetized with isoflurane inhalation (2-3 minutes) in a conduction chamberlocated in a fume hood. The right hindiimb of each rat was shaved and cleaned. A25 G needle attached with a Hamilton syringe pre-filled with testing solution was 5 used for the local injection. The solution was injected onto the subperiosteum ofthe anterior, mid-diaphyseal région of fémur in a volume of 5 to 10 ul for variousdays. On day 15, the rats were sacrificed and the fémurs were collected foranalysis. (See, e.g., Μ. E. Joyce, A.B. Roberts, M.B. Sporn and M. Bolander,“Transforming growth factor-β and the initiation of chondrogenesis and 10 osteogenesis in the rat fémur,” The Journal of Cell Biology 110:2195-2207 (1990).)IV. Study Protocol and Results in the Rat Periosteal Injection Model
On day one, the right fémurs of male Sprague-Dawley rats received singleinjection of vehicle or test compound in a polymer formulation. The test compoundwas the sodium sait of (3-(((4-fezf-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)- 15 methyl)-phenoxy)-acetic acid. On day 15, ail rats were sacrificed and the rightfémurs were collected for analysis. Periosteal bone induction was assessed byusing radiography and dual-energy X-ray absorptiometry (DEXA). Radiographyshowed new bone formation located on the anterior aspect of the right fémurstreated with the test compound. The bone minerai content (BMC) of the injected 20 région of the fémur (area between lesser trochanter and mid-shaft of the fémur) asassessed by DEXA was significantly increased in the rats treated with the testcompound as compared with those treated with vehicle (see some examples ofthese formulations listed in Table A below). 012731
TABLE A
Formulation Drug Load (mgA/ml) X-Rayefficacy(positive/total #) BMC (%increase vs. Veh) 47% 50:50 PLGH (RG502H Grade) + 3%PLG-PEG (IV=0.79dL/g)/50% NMP 0 0/10 37% PLGH (RG503H Grade)/63% NMP 0 0/10 47% 50:50 PLGH (RG502H Grade) + 3%PLG-PEG (IV=0.79dL/g)/50% NMP 50 9/10 +21 47% 50:50 PLGH (RG503H Grade) + 3%PLG-PEG (IV=0.79dL/g)/50% NMP 50 9/10 +23 45% 50:50 PLGH (RG504HGrade)/55%NMP 50 10/10 +19 45% 50:50 PLGH (RG502H Grade)/5%PLG-PEG/50% NMP 50 8/9 +26 50% 50:50 PLGH (RG502H Grade)/50%NMP 50 5/9 +19 37% 50:50 PLGH (RG503H Grade)/63%NMP 50 7/9 +15 45% 50:50 PLGH (RG502H Grade)/5%PLG-PEG/50% NMP 5 9/10 +18 47% PLGH (RG503H Grade) + 3% PLG-PEG/50% NMP 5 6/8 +18
Efficacy of Test Compound in a Slow-Release Matrix Formulation in Dog
Segmentai Defect Mode! 5 The uinar segmentai defect mode! was used to test the efficacy of a single dose of the test compound (which was the sodium sait of (3-(((4-ferî-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid) in a PLGH formulation(50% 50:50 PLGH (RG502H Grade)/50% NMP). The protocol was modified asfollows: With animais under general anesthésia, the foreieg was prepped and 10 draped in stérile fashion. A latéral incision approximately 10 cm in length was madeand the ulna was exposed extraperiostally. Periosteum was eut and moved to theproximal and distal parts of the incision. Then a 1.5 cm segmentai defect was madein the midulna using a pendular saw. The radius and the remaining interossealmembrane we.re left intact. The defect site was irrigated with saline to remove bone 15 débris. The site was then filied with test compound in a slow-release matrix formulation, as described above. The dogs were divided into the following groupe. 012731 -23-
Table 1.
Groups Treatment A 1 ml of carrier B 50 mg of test compound (1 ml of 50 mg/ml formulation). C 10 mg of test compound (1 ml of 10 mg/ml formulation). D 10 mg of test compound (0.2 ml of 50 mg/ml formulation).
Radiographs of the forelimbs were obtained immediately following surgeryand every two weeks thereafter until the termination of the study. Radiographs were 5 graded on a 0 to 6 scale (Table 2).
Table 2. Radiographie Grading Scale
Grade 0 No change from immédiate postoperative appearance Grade 1 Trace of radiodense material in defects Grade 2 Flocculent radiodensity with flecks of calcification and no defectbridging Grade 3 Defect bridged at least one point with material of nonuniformradiodensity Grade 4 Defect bridged in médial and latéral sides with material of uniformradiodensity, eut ends of cortex remain visible Grade 5 Same as Grade 3, at least one of four cortices obscured by newbone Grade 6 Defect bridged by uniform new bone, eut ends of cortex not seen
It was observed that a single application of test compound in a slow release10 matrix formulation induced complété rebridgement in dogs présent in groups B, C and D. The newly formed bone remodeled back to the same shape and size^as thecontralatéral bone by week 24. Even after 24 weeks, ulna treated with vehicle didnot show any healing as assessed by radiography.
Similar results were obtained when the dogs were treated with either 10mg15 of the 50 mg/ml (0.2 ml final volume) of the test compound or with 1 ml of the 10mg/ml formulation (groups C and D). Overall between 70 -75% of the treatedanimais healed compared to none for the vehicle treated Controls (Table 3). 012731 -24-
Table 3. Results from the Dog Segmentai Defect Model
Groups Radiographie Scale Complété rebridging /number of dogs A Very Poorhealing.RadiographieScale between 0and 1 0Z8 B Radiographiescale between 5and 6 for twodogs. The othertwo werebetween 1 and 2. 2/4 C Scale of 5 to 6for 9 dogs. Scaleof 1 to 2 for onedog. Two dogsdid not respond. 9/12 D Scale of 5 to 6.One dog did notrespond. 3/4
When the test compound (50 mg/ml) was tested in the above model in aformulation containing 50% 50:50 PLGH (RG503H Grade)/50% NMP, it did not 5 work well. Union was achieved in some dogs, but it was delayed compared to dogstreated with the formulation containing the RG502H Grade of PLGH.
The Canine Tibial Osteotomy Model
Normal fracture healing usually represents a biologically optimum healingprocess, as a resuit detecting an accélération of healing in pre-clinical models that 10 heal rapidly is both difficult and challenging. The test compound (which was thesodium sait of (3-(((4-ferf-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic acid) in a PLGH formulation (50% 50:50 PLGH (RG502HGrade)/50% NMP) was studied to détermine its effect on accelerating healing in arapidly healing canine osteotomy model. Enhancement of healing in this model 15 supports potential applications of the test compound to heal normal fractures in humans since humans tend to heal fractures more slowly. 012731 -25-
Beagle male dogs 12 ± 3 kg, 14 months of âge were used for the study.Dogs were divided into four groups of three to four animais each.
Table 4.
Groups Treatment A No treatment B 0.5 ml carrier C 5 mg of test compound (0.5 ml of 10 mg/ml formulation). D 25 mg of test compound (0.5 ml of 50 mg/ml formulation).
With animais under general anesthésia, the hindleg was prepped and 5 draped in stérile fashion. A latéral incision approximateiy 4 cm in length was made.Surgical osteotomy was made on the distal portion of the dog tibia using a Giglisaw. The defect was stabilized using an AO plate. The fibula and the remaininginterosseal membrane was left intact and the defect site was irrigated with saline toremove bone débris. The site was then filled with carrier as described above. 10 Following surgery, animais were allowed full weight-bearing activity, and water andfood ad libitum. Radiographs of the hindlimbs were obtained immediately followingsurgery and every two weeks thereafter until the termination of the study.Radiographs were graded on a 0 to 6 scaie.
Table 5. Results from the Dog Tibial Osteotomy Study
Groups Radiographie Scale Rebridging /number ofdogs A Between 2 to 3. 0/3 B Between 2 to 3. 0/3 C Between 4 to 5. 4/4 D Between 4 to 5. 3/4 15 None of the four dogs rebridged the defect area within the time frame of 8 weeks in groups A and B. This timing was chosen for the termination of the study toobtain différences between treated groups of animais. Four out of four animaisshowed significant rebridgement within the time period of 8 weeks in group C. Ingroup D, one animal was a non-responder, however, the other three showed 20 significant healing (Table 5).
Claims (15)
1. A pharmaceutical composition suitable for in situ formation of an implant in apatient comprising: (a) a pharmaceutically acceptable, biodégradable thermoplastic polymer orcopolymer that is insoluble in aqueous or body fluid; (b) a biocompatible organic solvent which solubilizes the thermoplastic polymer,is dispersible in situ in body fluid, is highly soluble in water and is capable ofdissipating from the polymer System into surrounding tissue fluid whereupon thethermoplastic polymer forms the implant; and (c) a therapeutically effective amount of a compound or a pharmaceuticallyacceptable sait thereof selected from the group consisting of: (3-(((4-ferf-butyl-benzyl)-(pyridine-3-suIfonyl)-amino)-methyl)-phenoxy)-acetic acid; 7-[(4-butyI-benzyl)-methanesulfonyl-amino]-heptanofc acid; and 7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid.
-2. The composition of claim 1 wherein the compound is the sodium sait of (3-(((4- fe/f-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyi)-phenoxy)-acetic acid or the freeacid of (3-(((4-fezf-butyl-benzyI)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-aceticacid.
3. The composition of claim 2 wherein the compound is the sodium sait of (3-(((4-ferf-butyl-benzyl)-(pyridine-3-sulfonyI)-amino)-methyl)-phenoxy)-acetic acid lyophile.
4. The composition of claim 2 wherein the amount of the compound is betweenabout 5 to about 50 mgA/ml of the composition.
" 5. The composition of claim 4 wherein the amount of the compound is about 5,10or 50 mgA/ml of the composition.
6. The composition of claim 1 wherein the polymer is selected from the groupconsisting of polylactîdes, polyglycolides and copolymers thereof.
7. The composition of claim 6 wherein the copolymer has an inhérent viscosity ofabout 0.20 dl/g to about 0.40 dl/g.
8. The composition of claim 6 wherein the copolymer is poly-lactic-co-glycolic acid(PLGH).
9. The composition of claim 8 wherein the ratio of lactic acid to glycolic acid isabout 1 to about 1. 012731 -27-
10. The composition of daim 1,2 or 3, wherein the solvent is N-methyl-2-pyrrolidone (NMP).
11. The composition of claim 1,2 or 3, wherein the copolymer is poly-lactic-co-glycolic acid (PLGH) and wherein the solvent is N-methyl-2-pyrrolidone (NMP).
12. The composition of claim 11 wherein the weight percentage of PLGH to NMPin solution is between about 30% and about 60% of PLGH to between about 70%and about 40% of NMP.
13. The composition of claim 12 wherein the weight percentage of PLGH to NMPin solution is about 50% PLGH to about 50% NMP.
14. A pharmaceutical kit suitable for in situ formation of a biodégradable implantin the body of a patient, which comprises: A) a device containing a compound or a pharmaceutically acceptable sait thereofselected from the group consisting of: (3-(((4-fe/ï-butyl-benzyl)-(pyridine-3-suIfonyl)-amino)-methyI)-phenoxy)-acetic acid; _ 7-[(4-butyl-benzyi)-methanesulfonyl-amino]-heptanoic acid; and 7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesuifonyl-amino}-heptanoicacid; and B) a device containing a flowable composition of a biodégradable,biocompatible, pharmaceutically acceptable thermoplastic polymer that is insolublein aqueous or body fluid and a pharmaceutically acceptable solvent that isdispersibie in situ in body fluid and is highly water soluble, wherein theconcentrations and formulas of the polymer and the solvent in the flowablecomposition are effective to form an implant in situ when the flowable compositioncontacts body fluid; C) wherein the devices hâve an outlet for the compound or the flowablecomposition, an ejector for expeiling the compound or the flowable compositionthrough the outlet and a hollow tube fitted to the outlet; and wherein the contents ofthe two devices are mixed together immediately prior to delivering the contents ofthe device containing the mixture into the body of the patient.
15. A method of forming an implant in-situ, in a iiving body, comprising the stepsof: (a) dissolving a non-reactive, water-insoluble biodégradable polymer in a biocompatible, highly water soluble organic solvent that is dispersibie in body fluid in situ to form a flowable composition; 012731 -28- (b) adding an effective amount of a compound to the fiowable composition toprovide a pharmaceutical composition; (c) placing the pharmaceutical composition within the body; and (d) allowing the solvent to dissipate to produce a solid or gel implant which 5 releases the compound by diffusion, érosion or a combination of diffusion and érosionas the implant biodegrades; wherein the compound or a pharmaceutically acceptable sait thereof is selectedfrom the group consisting of: (3-(((4-ferf-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-methyl)-phenoxy)-acetic10 acid; 7-[(4-butyl-benzyJ)-methanesulfonyl-amino]-heptanoic acid; and7-{[2-(3,5-dichloro-phenoxy)-ethyI]-methanesulfonyl-amino}-heptanoic acid;wherein the polymer is selected from the group consisting of polyiactides and copolymers thereof with glycolide; and15 wherein the solvent is N-methyl-2-pyrrolidone (NMP).
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33725501P | 2001-11-30 | 2001-11-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA12731A true OA12731A (en) | 2006-06-28 |
Family
ID=23319774
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| OA1200400150A OA12731A (en) | 2001-11-30 | 2002-11-20 | Controlled release polymeric compositions of bone growth promoting compounds. |
Country Status (34)
| Country | Link |
|---|---|
| US (2) | US20030104031A1 (en) |
| EP (1) | EP1448166A1 (en) |
| JP (1) | JP4903985B2 (en) |
| KR (1) | KR100629380B1 (en) |
| CN (1) | CN1599598A (en) |
| AP (1) | AP1781A (en) |
| AR (1) | AR037462A1 (en) |
| AU (2) | AU2002347502A1 (en) |
| BR (1) | BR0214610A (en) |
| CA (1) | CA2468703C (en) |
| DO (1) | DOP2002000534A (en) |
| EA (1) | EA011350B1 (en) |
| EC (1) | ECSP045124A (en) |
| GE (1) | GEP20063951B (en) |
| GT (1) | GT200200242A (en) |
| HR (1) | HRP20040486A2 (en) |
| HU (1) | HUP0402135A3 (en) |
| IL (1) | IL161835A0 (en) |
| IS (1) | IS7217A (en) |
| MA (1) | MA27084A1 (en) |
| MX (1) | MXPA04003723A (en) |
| NO (1) | NO20042273L (en) |
| NZ (1) | NZ533115A (en) |
| OA (1) | OA12731A (en) |
| PA (1) | PA8559001A1 (en) |
| PE (1) | PE20030581A1 (en) |
| PL (1) | PL370085A1 (en) |
| SV (1) | SV2004001421A (en) |
| TN (1) | TNSN04096A1 (en) |
| TW (1) | TW200300695A (en) |
| UA (1) | UA76792C2 (en) |
| WO (1) | WO2003045351A1 (en) |
| YU (1) | YU35004A (en) |
| ZA (1) | ZA200402755B (en) |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7074425B2 (en) * | 2002-09-26 | 2006-07-11 | Bonewax, Llc | Hemostatic compositions and methods |
| US20040260398A1 (en) * | 2003-02-10 | 2004-12-23 | Kelman David C. | Resorbable devices |
| GB0307011D0 (en) | 2003-03-27 | 2003-04-30 | Regentec Ltd | Porous matrix |
| CN1909911A (en) * | 2003-10-01 | 2007-02-07 | 浩鼎生技公司 | Treatment of a condition in a mammal with adminisration of aminosugar and uses thereof |
| GB0329654D0 (en) | 2003-12-23 | 2004-01-28 | Smith & Nephew | Tunable segmented polyacetal |
| US8641738B1 (en) | 2004-10-28 | 2014-02-04 | James W. Ogilvie | Method of treating scoliosis using a biological implant |
| US8123787B2 (en) | 2004-10-28 | 2012-02-28 | Ogilvie James W | Method of treating scoliosis using a biological implant |
| WO2007020432A2 (en) * | 2005-08-18 | 2007-02-22 | Smith & Nephew, Plc | High strength devices and composites |
| CN100443065C (en) * | 2006-01-26 | 2008-12-17 | 上海交通大学 | Composite system implant unit for maxillofacial bone |
| ATE493081T1 (en) | 2006-11-30 | 2011-01-15 | Smith & Nephew Inc | FIBER REINFORCED COMPOSITE MATERIAL |
| WO2008129245A1 (en) | 2007-04-18 | 2008-10-30 | Smith & Nephew Plc | Expansion moulding of shape memory polymers |
| EP2142227B1 (en) | 2007-04-19 | 2012-02-29 | Smith & Nephew, Inc. | Multi-modal shape memory polymers |
| DE602008006181D1 (en) | 2007-04-19 | 2011-05-26 | Smith & Nephew Inc | GRAFT FIXATION |
| US8062739B2 (en) * | 2007-08-31 | 2011-11-22 | Zimmer, Inc. | Hydrogels with gradient |
| US20090181068A1 (en) * | 2008-01-14 | 2009-07-16 | Dunn Richard L | Low Viscosity Liquid Polymeric Delivery System |
| EP2172189A1 (en) * | 2008-10-01 | 2010-04-07 | Novartis AG | Pharmaceutical Compositions |
| PT2323623T (en) | 2008-08-12 | 2016-11-04 | Novartis Ag | Pharmaceutical compositions |
| US9642658B2 (en) | 2008-10-15 | 2017-05-09 | Orthoclip Llc | Device and method for delivery of therapeutic agents via internal implants |
| WO2010045487A1 (en) * | 2008-10-15 | 2010-04-22 | Palmetto Biomedical, Inc. | Device and method for delivery of therapeutic agents via internal implants |
| EP2464389A2 (en) | 2009-08-06 | 2012-06-20 | Koninklijke Philips Electronics N.V. | Oncology therapies employing radioactive seeds |
| US20130071403A1 (en) | 2011-09-20 | 2013-03-21 | Vical Incorporated | Synergistic anti-tumor efficacy using alloantigen combination immunotherapy |
| CN104189954B (en) * | 2014-09-19 | 2017-03-29 | 中国科学院长春应用化学研究所 | A kind of in-situ solidifying tissue engineering bracket and preparation method thereof |
| RU2571548C1 (en) * | 2014-12-17 | 2015-12-20 | Федеральное государственное бюджетное учреждение науки Институт органической и физической химии им. А.Е. Арбузова Казанского научного центра Российской академии наук | Veterinary implantable retard drug (versions) |
| US10406098B2 (en) | 2015-11-16 | 2019-09-10 | Evonik Roehm Gmbh | Injection solution comprising a non-nucleoside reverse-transcriptase inhibitor and poly(lactide-co-glycolide) |
| CN109498852B (en) * | 2018-12-29 | 2022-06-24 | 广州噢斯荣医药技术有限公司 | Biodegradable material for treating orthopedic diseases and application thereof |
| EP4054591A1 (en) | 2019-11-04 | 2022-09-14 | Astrazeneca AB | Combination therapy for treating cancer |
| EP4255357A1 (en) | 2020-12-29 | 2023-10-11 | Sino Medical Sciences Technology Inc. | Drug eluting stent |
| WO2024089418A1 (en) | 2022-10-24 | 2024-05-02 | Cancer Research Technology Limited | Tumour sensitisation to checkpoint inhibitors with redox status modifier |
| WO2024089417A1 (en) | 2022-10-24 | 2024-05-02 | Memorial Sloan-Kettering Cancer Center | Tumour stratification for responsiveness to an immune checkpoint inhibitor |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE241394T1 (en) * | 1994-04-08 | 2003-06-15 | Atrix Lab Inc | ASSOCIATED POLYMER SYSTEM FOR USE WITH A MEDICAL DEVICE |
| WO1996021427A1 (en) | 1995-01-09 | 1996-07-18 | Atrix Laboratories, Inc. | Liquid polymer delivery system |
| EP0959873B1 (en) * | 1996-12-20 | 2006-03-01 | ALZA Corporation | Gel composition and methods |
| UA59384C2 (en) * | 1996-12-20 | 2003-09-15 | Пфайзер, Інк. | Preventing bone mass loss and recovery thereof by means of prostaglandin agonists |
| UA67754C2 (en) * | 1997-10-10 | 2004-07-15 | Пфайзер, Інк. | Prostaglandin agonists and use thereof for the treatment of bone disorders |
| US7128927B1 (en) * | 1998-04-14 | 2006-10-31 | Qlt Usa, Inc. | Emulsions for in-situ delivery systems |
| US6143314A (en) * | 1998-10-28 | 2000-11-07 | Atrix Laboratories, Inc. | Controlled release liquid delivery compositions with low initial drug burst |
-
2002
- 2002-11-20 EP EP02783436A patent/EP1448166A1/en not_active Withdrawn
- 2002-11-20 IL IL16183502A patent/IL161835A0/en unknown
- 2002-11-20 WO PCT/IB2002/004965 patent/WO2003045351A1/en active IP Right Grant
- 2002-11-20 OA OA1200400150A patent/OA12731A/en unknown
- 2002-11-20 NZ NZ533115A patent/NZ533115A/en unknown
- 2002-11-20 AP APAP/P/2004/003037A patent/AP1781A/en active
- 2002-11-20 CN CNA028239687A patent/CN1599598A/en active Pending
- 2002-11-20 HU HU0402135A patent/HUP0402135A3/en unknown
- 2002-11-20 KR KR1020047008243A patent/KR100629380B1/en not_active IP Right Cessation
- 2002-11-20 EA EA200400608A patent/EA011350B1/en not_active IP Right Cessation
- 2002-11-20 AU AU2002347502A patent/AU2002347502A1/en not_active Abandoned
- 2002-11-20 YU YU35004A patent/YU35004A/en unknown
- 2002-11-20 PL PL02370085A patent/PL370085A1/en not_active Application Discontinuation
- 2002-11-20 BR BR0214610-0A patent/BR0214610A/en not_active IP Right Cessation
- 2002-11-20 CA CA002468703A patent/CA2468703C/en not_active Expired - Fee Related
- 2002-11-20 MX MXPA04003723A patent/MXPA04003723A/en active IP Right Grant
- 2002-11-20 GE GE5596A patent/GEP20063951B/en unknown
- 2002-11-20 JP JP2003546854A patent/JP4903985B2/en not_active Expired - Fee Related
- 2002-11-20 UA UA20040504054A patent/UA76792C2/en unknown
- 2002-11-25 US US10/303,590 patent/US20030104031A1/en not_active Abandoned
- 2002-11-27 PE PE2002001144A patent/PE20030581A1/en not_active Application Discontinuation
- 2002-11-27 GT GT200200242A patent/GT200200242A/en unknown
- 2002-11-28 PA PA20028559001A patent/PA8559001A1/en unknown
- 2002-11-28 DO DO2002000534A patent/DOP2002000534A/en unknown
- 2002-11-28 AR ARP020104597A patent/AR037462A1/en unknown
- 2002-11-29 TW TW091134882A patent/TW200300695A/en unknown
- 2002-11-29 SV SV2002001421A patent/SV2004001421A/en not_active Application Discontinuation
-
2004
- 2004-04-07 IS IS7217A patent/IS7217A/en unknown
- 2004-04-08 ZA ZA200402755A patent/ZA200402755B/en unknown
- 2004-05-20 MA MA27688A patent/MA27084A1/en unknown
- 2004-05-28 EC EC2004005124A patent/ECSP045124A/en unknown
- 2004-05-28 TN TNP2004000096A patent/TNSN04096A1/en unknown
- 2004-05-31 HR HR20040486A patent/HRP20040486A2/en not_active Application Discontinuation
- 2004-06-01 NO NO20042273A patent/NO20042273L/en not_active Application Discontinuation
-
2008
- 2008-10-24 US US12/257,803 patent/US8017144B2/en not_active Expired - Fee Related
-
2009
- 2009-01-13 AU AU2009200125A patent/AU2009200125B2/en not_active Ceased
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2009200125B2 (en) | Controlled release polymeric compositions of bone growth promoting compounds | |
| JP6087886B2 (en) | Leuprolide polymer delivery formulation with improved efficacy | |
| US5945115A (en) | Polymeric compositions useful as controlled release implants | |
| EP2575890B1 (en) | Antipsychotic injectable depot composition | |
| PT2244752E (en) | Low viscosity liquid polymeric delivery system | |
| EA024211B1 (en) | Methods for the preparation of injectable depot compositions | |
| AU2005315823B2 (en) | In-situ forming implant for animals | |
| JP2005538052A (en) | Injection formulation | |
| US20220152270A1 (en) | Long lasting biodegradable polymer based in-situ forming implant for treatment of bone injuries | |
| US20090292013A1 (en) | In-Situ Forming Implant for Animals | |
| US20180318344A1 (en) | Zinc or manganese compounds as therapeutic adjuncts for cartilage regeneration and repair |